This invention is in the area of methods and compositions for the treatment of a host infected with hepatitis delta virus (also referred to as xe2x80x9cHDVxe2x80x9d) that includes administering an effective amount of a defined xcex2-L-2xe2x80x2-deoxy-nucleoside or a pharmaceutically acceptable salt or prodrug thereof.
Type D hepatitis, the most severe form of viral hepatitis, is caused by infection with hepatitis D (delta) virus (HDV), a sub-viral satellite of hepatitis B virus (HBV) (Smedile, A. et al. Prog Liver Dis 1994, 12, 157-75). Compared with other agents of viral hepatitis, acute HDV infection is more often associated with fulminant hepatitis, a rapidly progressive, often fatal form of the disease in which massive amounts of the liver are destroyed. Chronic type D hepatitis is typically characterized by necroinflammatory lesions, similar to chronic HBV infection, but is more severe, and frequently progresses rapidly to cirrhosis and liver failure, accounting for the disproportionate association of chronic HDV infection with terminal liver disease (Smedile, A. et al. Prog Liver Dis 1994, 12, 157-75; Rizzetto, M. et al. Ann Intern Med 1983, 98, 437-41). Although HDV infection affects fewer individuals than HBV alone, the resulting acute or chronic liver failure is a common indication for liver transplantation in Europe as well as North America (Smedile, A. and Rizzetto, M. Int J Clin Lab Res 1992, 22, 211-215; Wright, T. L. and Pereira, B. Liver Transplant Surgery 1995, 1, 30-42). Chronic disease affects 15 million persons worldwide, about 70,000 of whom are in the U.S. The Center for Disease Control estimates 1,000 deaths annually in the U.S. due to HDV infection (Alter, M. J. and Hadler, S. C. Prog Clin Biol Res 1993, 382, 243-50; Alter, M. J. and Mast, E. E. Gastroenterol Clin North Am 1994, 23, 437-55).
There is currently no generally accepted effective therapy for type D hepatitis, and liver transplantation is the only option for the associated end-stage liver disease. Although interferon alpha has been moderately successful in treating some cases of type D hepatitis, the need for better treatment options is indicated by the very high doses required, variable responses, frequent relapse after cessation of treatment, and difficulties in drug administration (Thomas, H. C. et al. Prog Clin Biol Res 1987, 234, 277-90; Hoofnagle, J. et al. Prog Clin Biol Res 1987, 234, 291-8; Rosina, F. et al. Prog Clin Biol Res 1987, 234, 299-303; Rosina, F. et al. Hepatology 1991, 13, 1052-6; Farci, P. et al. N Engl J Med 1994, 330, 88-94; Hadziyannis, S. J. J Hepatol 1991, 13(Suppl 1), S21-6; Di Marco, V. et al. J Viral Hepat 1996, 3, 123-8; Porres, J. C. et al. J Hepatol 1989, 9, 338-44).
The HDV virion is composed of a ribonucleoprotein core and an envelope. The core contains HDV-RNA, and hepatitis delta antigen (HDAg), which is the only protein encoded by this virus (Wang, K. S. et al. Nature 1986, 323, 508-14). The envelope is formed by the surface antigen protein (hepatitis B surface antigen, or HBsAg) of the helper virus, hepatitis B (Bonino, F. Infect Immun 1984, 43, 1000-5; Bonino, F. et al. Hepatology 1981, 1, 127-31; Bonino, F. et al. J Virol 1986, 58, 945-50). The envelope is the sole helper function provided by HBV. HDV is able to replicate its RNA within cells in the absence of HBV (Kuo, M. Y. et al. J Virol 1989, 63, 1945-50), but requires HBsAg for packaging and release of HDV virions (Wu, J. C. et al. J Virol 1991, 65, 1099-104; Ryu, W. S. et al. J Virol 1992, 66, 2310-2315), as well as for infectivity (Sureau, C., et al. J Virol 1992, 66, 1241-5). As a result of the dependence of HDV on HBV, HDV infects individuals only in association with HBV.
Lamivudine (xcex2-L-2xe2x80x2,3xe2x80x2-dideoxy-3xe2x80x2-thiacytidine, 3TC) is a synthetic nucleoside shown to be effective in treating HIV and HBV infection. See U.S. Pat. No. 5,539,116 to Liotta et al. Lamivudine is known to cause sustained suppression of HBV replication during treatment (Nevens, F. et al. Gastroenterology 1997, 113, 1258-1263). However, lamivudine does not improve disease activity or lower HDV-RNA levels in patients with chronic delta hepatitis (Lau, D. T. et al. Hepatology 1999, 30, 546-9). Lamivudine was recently approved in the U.S. and several other countries for treatment of chronic HBV infection. Prolonged treatment of chronic HBV carriers with lamivudine leads to decreased levels of HBV in serum and improved liver histology (Lai, C. L. et al. N Engl J Med 1998, 339, 61-8; Tyrrell, D. et al. Hepatology 1993, 18, 112A; Nevens, F. et al. Gastroenterology 1997, 113, 1258-63; Dienstag, J. L. et al. N Engl J Med 1995, 333, 1657-61). Despite the dramatic effects on HBV, lamivudine treatment of patients chronically infected with both HBV and HDV has little effect on circulating levels of HDV; more importantly, there is no improvement in disease activity even though HBV levels are suppressed (Honkoop, P. et al. Hepatology 1997, 24(Suppl), 1219 (Abstract); Lau, D. T. et al. Hepatology 1999, 30, 546-9).
Additional forms of treatment have been tried. For example, suramin in vitro blocks the entry of the virion into hepatocytes, but it is too toxic to be acceptable for long term use in humans (Smedile, A. et al. Prog Liver Dis 1994, 12, 157-75). Acyclovir enhances HDV replication in vitro (Smedile, A. et al. Prog Liver Dis 1994, 12, 157-75). Ribavirin did not significantly affect virological or biochemical parameters and had severe side-effects (Smedile, A. et al. Prog Liver Dis 1994, 12, 157-75). Synthetic analogs of thymosin have also been ineffective in the treatment of HDV infection (Smedile, A. et al. Prog Liver Dis 1994, 12, 157-75).
None of the described treatments for HDV infection are generally accepted as effective.
Because the woodchuck hepatitis virus (WHV) is closely related to HBV (ca. 85% nucleic acid homology), it has been widely used as a model for HBV infection and disease in its natural host, the eastern woodchuck (M. monax) (Gerin, J. L. Gastroenterol Jpn 1990, 25 Supp, 38-42; Tennant, B. C. et al. Viral Hepatitis and Liver Disease 1988, 462-464). Experimentally infected woodchucks have also been used extensively for analysis and development of anti-HBV therapeutics (Zahm, F. E. et al. Ital J Gastroenterol Hepatol 1998, 30, 510-6; Tennant, B. C. et al. Hepatology 1998, 28, 179-91; Mason, W. S. et al. Virology 1998, 245, 18-32; Korba, B. E. et al. Hepatology 1996, 23, 958-63; Hurwitz, S. et al. Antimicrob Agents Chemother 1998, 42, 2804-2809; Block, T. M. et al. Nat Med 1998, 4, 610-4; Cullen, J. M. et al. Antimicrob Agents Chemother 1997, 41, 2076-82; Fourel, G. et al. Nature 1990, 347, 294-8; Gangemi, J. et al. Antivir Therap 1997, 1, 64-70; Genovesi, E. V. et al. Antimicrob Agents Chemother 1998, 42, 3209-17; Korba, B. E. et al. Antiviral Res 2000, 45, 19-32; Cote, P. J. et al. Hepatolopy 2000, 31, 190-200; Korba, B. E. et al. Antiviral Therapy 2000, 5(2), 95-104; Korba, B. E. et al. Antimicrobial Agents and Chemotherapy 2000, 44(6), 1757-60; Korba, B. E. et al. Antimicrobial Agents and Chemotherapy 2000, 44(7), 1964-1969). The efficacy of several anti-HBV agents used to experimentally treat chronic WHV infection in woodchucks (araAMP, ribavirin, AZT, ACV, 3TC, famciclovir, FTC) has accurately paralleled the efficacy of these agents administered to HBV patients treated in the course of clinical trials. The similar efficacy observed in WHV infected woodchucks and HBV infected persons treated with anti-HBV agents demonstrates that the woodchuck animal model can be predictive for anti-HBV therapies in man (Zahm, F. E. et al. Ital J Gastroenterol Hepatol 1998, 30, 510-6; Tennant, B. C. et al. Hepatology 1998, 28, 179-91; Mason, W. S. et al. Virology 1998, 245, 18-32; Hurwitz, S. J. et al. Antimicrob Agents Chemother 1998, 42(11), 2804-2809; Fourel, G. et al. Nature 1990, 347, 294-8; Gangemi, J. et al. Antivir Therap 1997, 1, 64-70; Genovesi, E. V. et al. Antimicrob Agents Chemother 1998, 42, 3209-17; Korba, B. E. et al. Antiviral Res 2000, 45(1), 19-32; Korba, B. E. et al. Hepatology 2000, 32(4 Pt 1), 807-817; Korba, B. E. et al. Hepatology 2000, 31(5), 1165-1175; Korba, B. E. et al. Antiviral Therapy 2000, 5(2), 95-104). Like HBV, WHV can support HDV particle formation and infection, and the eastern woodchuck has been a useful model for HDV infection (Negro, F. et al. J Virol 1989, 63, 1612-8; Parana, R., Gerard, F., Lesbordes, J. L., Pichoud, C., Vitvitski, L., Lyra, L. G. and Trepo, C. J Hepatol 1995, 22, 468-73; Ciccaglione, A. R. et al. Arch Virol 1993, Suppl 8, 15-21; Bergmann, K. F. et al. J Immunol 1989, 143, 3714-21; Ponzetto, A. et al. Proc Natl Acad Sci USA 1984, 81, 2208-12; Ponzetto, A. et al. Prog Clin Biol Res 1987, 234, 37-46).
The dependence of HDV on its helper virus, HBV, could suggest that successful treatment of HDV infection would follow successful treatment of the supporting HBV infection, although, this does not appear to be the case, as illustrated by recent results obtained with the drug lamivudine (Glaxo-Wellcome, Inc.) (Honkoop, P. et al. Hepatology 1997, 24(Suppl), 1219 (Abstract); Lau, D. T. et al. Hepatology 1999, 30, 546-9). The lack of an effect of lamivudine on disease in HBV-HDV infected patients underscores the direct role of HDV in disease severity in such patients. Although lamivudine inhibits HBV and WHV replication, it does not affect the production of viral surface antigen (Lau, D. T. et al. Hepatology 1999, 30, 546-9; Doong, S. L. et al. Proc Natl Acad Sci USA 1991, 88, 8495-9; Korba, B. E. et al. Hepatology 2000, 32(4 Pt 1), 807-817; Korba, B. E. et al. Hepatology 2000, 31(5), 1165-1175). The life cycle of HBV and other representatives of this family of viruses (for example, WHV) is unique in that the process of replicating genomic copies of the virus and the production of viral proteins (for example, HBV or WHV surface antigens) are differentially regulated (Ganem, D. Hepadnaviridae In xe2x80x9cFields Virologyxe2x80x9d, Fields B N, Knipe D M, Howley P, ed. Lippincott-Raven 1996 Philadelphia, 2703-2737). Therefore, antiviral agents, such as synthetic nucleosides (for example, lamivudine) which target viral polymerases, may significantly inhibit HBV replication (for example, as measured by a reduction in viremia), but not affect the level of viral mRNA or viral protein production (for example, as measured by the levels of HBV surface antigen in plasma or serum). Because formation of the viral envelope by the surface antigen protein is the only HBV and WHV function important for HDV, the failure to inhibit HBsAg production might play a role in the failure of lamivudine to affect HDV replication and disease.
U.S. Pat. No. 5,747,044 discloses recombinantly produced immunogenic HDV polypeptides useful as vaccines.
U.S. Pat. No. 5,932,219 to Chiron discloses the entire genome of the hepatitis D virus, a family of cDNA replicas of the entire HDV genome, and teaches that portions of these cDNA sequences are useful as probes to diagnose the presence of virus in clinical samples. The patent also discloses proteins encoded by the cDNA that are useful in the production of vaccines. In particular, the ""219 patent discloses a vaccine for hepatitis D which incorporates the p24 and p27 viral polypeptides. U.S. Pat. No. 5,750,350 to Chiron claims a kit useful in the analysis of hepatitis D virus which includes a peptide encoded by ORF 5 of the HDV genome. U.S. Pat. No. 5,747,044 claims a recombinantly produced immunogenic particle which raises antibodies against HDV, wherein the particle includes an immunogenic polypeptide encoded within ORF 5 of the HDV nucleotide sequence or its complement.
U.S. Pat. No. 6,020,167 assigned to Medeva Holdings B. V. discloses a method for treating chronic hepatitis, and in particular, hepatitis B, that includes administering a composition containing HBsAg.
U.S. Pat. No. 5,770,584 discloses a method for treating hepatitis virus infection by administering alkyl lipids or alkyl lipid derivatives.
U.S. Pat. No. 4,619,896 discloses a process for unmasking delta antigen in the blood of an animal, that includes treating serum with a surfactant and optionally with an antibody-antigen dissociating agent. The blood derived delta antigen is used as a diagnostic agent in the detection and determination of different classes of antibodies to hepatitis D virus.
United States statutory invention registration H1,345 discloses a method for preventing or treating hepatitis virus by administering a protein-prenyl transferase inhibitor.
Sureau, et al. xe2x80x9cProduction of Infectious Hepatitis Delta Virus In Vitro and Neutralization with Antibodies Directed against Hepatitis B Virus Pre-S Antigensxe2x80x9d Journal of Virology 1992, 1241-1245 discloses that HDV particles produced in vitro are infectious and that (i) infectious particles are coated with HBV envelope proteins that contain the pre-S1 and pre-S2 regions, (ii) epitopes of the pre-S1 and pre-S2 domains of HBV envelope proteins are exposed at the surface of HDV particles, and (iii) that antibodies directed against those epitopes have neutralizing activity against HDV.
Recently, it has been reported that L-FMAU is a potent inhibitor of HDV in chronically infected animals. (Casey, J. L. et al., Antiviral Therapy 2000, 5(Suppl. 1), 32, Abstract 057).
The synthetic nucleosides xcex2-L-2xe2x80x2-deoxycytidine (xcex2-L-2xe2x80x2-dC), xcex2-L-2xe2x80x2-deoxythymidine (xcex2-L-dT) and xcex2-L-2xe2x80x2-deoxyadenosine (xcex2-L-2xe2x80x2-dA), are also known in the art. Antonin Holy first disclosed xcex2-L-dC and xcex2-L-dT in 1972, xe2x80x9cNucleic Acid Components and Their Analogs. CLIII. Preparation of 2xe2x80x2-deoxy-L-Ribonucleosides of the Pyrimidine Seriesxe2x80x9d Collect Czech Chem Commun 1972, 37(12), 4072-87. Morris S. Zedeck et al. first disclosed xcex2-L-dA for the inhibition of the synthesis of induced enzymes in Pseudomonas testosteroni (Mol Phys 1967, 3(4), 386-95).
Certain 2xe2x80x2-deoxy-xcex2-L-erythro-pentofuranonucleosides are known to have anti-neoplastic and selected antiviral activities. Verri et al. disclose the use of 2xe2x80x2-deoxy-xcex2-L-erythro-pentofuranonucleosides as antineoplastic agents and as anti-herpetic agents (Mol Pharmacol 1997, 51(1), 132-138 and Biochem J 1997, 328(1), 317-20). Saneyoshi et al. demonstrate the use of 2xe2x80x2-deoxy-L-ribonucleosides as reverse transcriptase (I) inhibitors for the control of retroviruses and for the treatment of AIDS, Japanese Kokai Tokyo Koho JP 06293645 (1994).
Giovanni et al. tested 2xe2x80x2-deoxy-xcex2-L-erythro-pentofuranonucleosides against partially pseudorabies virus (PRV) (Biochem J 1993, 294(2), 381-5).
Chemotherapeutic uses of 2xe2x80x2-deoxy-xcex2-L-erythro-pentofuranonucleosides were studied by Tyrsted et al. Biochem Biophys Acta 1968, 155(2), 619-22 and Bloch, et al. J Med Chem 1967, 10(5), 908-12.
xcex2-L-2xe2x80x2-deoxythymidine (xcex2-L-dT) is known in the art to inhibit herpes simplex virus type 1 (HSV-1) thymidine kinase (TK). Iotti et al., WO 92/08727, teaches that xcex2-L-dT selectively inhibits the phosphorylation of D-thymidine by HSV-1 TK, but not by human TK. Spaldari et al. reported that L-thymidine is phosphorylated by herpes simplex virus type 1 thymidine kinase and inhibits viral growth, J Med Chem 1992, 35(22), 4214-20.
The synthetic nucleosides xcex2-L-2xe2x80x2-deoxycytidine (xcex2-L-2xe2x80x2-dC), xcex2-L-2xe2x80x2-deoxythymidine (xcex2-L-dT), xcex2-L-2xe2x80x2-deoxyinosine (xcex2-L-dI) and xcex2-L-2xe2x80x2-deoxyadenosine (xcex2-L-2xe2x80x2-dA) have recently been disclosed in the art for the treatment of hepatitis B virus. Gilles Gosselin et al. disclosed the use of xcex2-L-dT, xcex2-L-dA, xcex2-L-dC and xcex2-L-dI, and pharmaceutically acceptable salts and prodrugs thereof for the treatment of hepatitis B virus in WO 00/09531 (PCT/US99/18149).
PCT/US01/09987 filed by Georgetown University, Cornell University and the University of Georgia Research Foundation, Inc. describes that the administration of a nucleoside or nucleoside analog that substantially reduces the level of hepatitis B surface antigen (referred to therein as HBsAg) in a host is useful in the treatment of hepatitis delta viral infection in that host. In one embodiment PCT/US01/09987 describes that 2xe2x80x2-fluoro-5-methyl-beta-L-arabinofuranosyluridine (L-FMAU) significantly reduces the level of hepatitis B surface-antigen, and thus is useful in the treatment of hepatitis delta infections.
Because of the large number of persons infected with hepatitis delta virus, the devastating effects of hepatitis delta virus infection on the individual, and the lack of effective treatments, there is a critical need for new and effective for the treatment of hepatitis delta virus infection.
Therefore, it is an object of the present invention to provide methods for the treatment of a host, including a human, infected with hepatitis delta virus.
A method for the treatment of hepatitis delta infection in humans and other hosts is disclosed that includes administering an effective amount of a biologically active 2xe2x80x2-deoxy-xcex2-L-erythro-pentofuranonucleoside (referred to alternatively herein as a xcex2-L-d-nucleoside or a xcex2-L-2xe2x80x2-d-nucleoside) or a pharmaceutically acceptable salt or prodrug thereof, administered either alone or in combination or alternation, optionally in a pharmaceutically acceptable carrier. The term 2xe2x80x2-deoxy, as used in this specification, refers to a nucleoside that has no substituent in the 2xe2x80x2-position.
The disclosed 2xe2x80x2-deoxy-xcex2-L-erythro-pentofuranonucleosides, or pharmaceutically acceptable prodrugs or salts or pharmaceutically acceptable formulations containing these compounds are useful in the prevention and treatment of hepatitis D infections and other related conditions such as chronic liver inflammation caused by HDV, cirrhosis, acute hepatitis, fulminant hepatitis, chronic persistent hepatitis, and fatigue. These compounds or formulations can also be used prophylactically to prevent or retard the progression of clinical illness in individuals who are infected with HDV or who have been exposed to HDV.
In one embodiment of the present invention, the 2xe2x80x2-deoxy-xcex2-L-erythro-pentofuranonucleoside derivative is a compound of the formula: 
wherein R1 is selected from the group consisting of H, straight chained, branched or cyclic alkyl, CO-alkyl, CO-aryl, CO-alkoxyalkyl, CO-aryloxyalkyl, CO-substituted aryl, alkylsulfonyl, arylsulfonyl, aralkylsulfonyl, amino acid residue, mono, di, or triphosphate, or a phosphate derivative; and
BASE is a purine or pyrimidine base that may optionally be substituted.
In another embodiment of the present invention, the 2xe2x80x2-deoxy-xcex2-L-erythro-pentofuranonucleoside derivative is xcex2-L-2xe2x80x2-deoxypurine or a pharmaceutically acceptable salt or prodrug thereof, of the formula: 
wherein R1 is selected from the group consisting of H; straight chained, branched or cyclic alkyl, CO-alkyl, CO-aryl, CO-alkoxyalkyl, CO-aryloxyalkyl, CO-substituted aryl, alkylsulfonyl, arylsulfonyl, aralkylsulfonyl, amino acid residue, mono, di, or triphosphate, or a phosphate derivative;
Y is OR3, NR3R4 or SR3; and
X1 and X2 are independently selected from the group consisting of H, straight chained, branched or cyclic alkyl, CO-alkyl, CO-aryl, CO-alkoxyalkyl, halogen, OR5, NR5NR6 or SR5; and
R3, R4, R5 and R6 are independently H, straight chained, branched or cyclic alkyl, CO-alkyl, CO-aryl, CO-alkoxyalkyl, CO-aryloxyalkyl, CO-substituted aryl, alkylsulfonyl, arylsulfonyl, aralkylsulfonyl, amino acid residue, mono, di, or triphosphate, or a phosphate derivative.
In a particular embodiment, the 2xe2x80x2-deoxy-xcex2-L-erythro-pentofuranonucleoside derivative is xcex2-L-2xe2x80x2-deoxyadenosine or a pharmaceutically acceptable salt or prodrug thereof, of the formula: 
wherein R1 is H, mono, di or tri phosphate, acyl, alkyl, or a stabilized phosphate derivative (to form a stabilized nucleotide prodrug).
In a preferred embodiment, R1 is H.
In another particular embodiment, the 2xe2x80x2-deoxy-xcex2-L-erythro-pentofuranonucleoside derivative is xcex2-L-2xe2x80x2-deoxyguanosine or pharmaceutically acceptable salt or prodrug thereof of the formula: 
wherein R1 is H, mono, di or tri phosphate, acyl, alkyl, or a stabilized phosphate derivative (to form a stabilized nucleotide prodrug).
In another particular embodiment, the 2xe2x80x2-deoxy-xcex2-L-erythro-pentofuranonucleoside derivative is xcex2-L-2xe2x80x2-deoxyinosine or pharmaceutically acceptable salt or prodrug thereof of the formula: 
wherein R1 is H, mono, di or tri phosphate, acyl, alkyl, or a stabilized phosphate derivative (to form a stabilized nucleotide prodrug).
In another embodiment of the present invention, the 2xe2x80x2-deoxy-xcex2-L-erythro-pentofuranonucleoside derivative is xcex2-L-2xe2x80x2-deoxypyrimidine or a pharmaceutically acceptable salt or prodrug thereof, of the formula: 
wherein R1 is selected from the group consisting of H, straight chained, branched or cyclic alkyl, CO-alkyl, CO-aryl, CO-alkoxyalkyl, CO-aryloxyalkyl, CO-substituted aryl, alkylsulfonyl, arylsulfonyl, aralkylsulfonyl, amino acid residue, mono, di, or triphosphate, or a phosphate derivative;
Y is OR3, NR3R4 or SR3; and
X1 is selected from the group consisting of H, straight chained, branched or cyclic alkyl, CO-alkyl, CO-aryl, CO-alkoxyalkyl, halogen, OR5, NR5NR6 or SR5; and
R3, R4, R5 and R6 are independently H, straight chained, branched or cyclic alkyl, CO-alkyl, CO-aryl, CO-alkoxyalkyl, CO-aryloxyalkyl, CO-substituted aryl, alkylsulfonyl, arylsulfonyl, aralkylsulfonyl, amino acid residue, mono, di, or triphosphate, or a phosphate derivative.
In one particular embodiment, the 2xe2x80x2-deoxy-xcex2-L-erythro-pentofuranonucleoside derivative is xcex2-L-2xe2x80x2-deoxycytidine or pharmaceutically acceptable salt or prodrug thereof of the formula: 
wherein R1 is H, mono, di or tri phosphate, acyl, alkyl, or a stabilized phosphate derivative (to form a stabilized nucleotide prodrug).
In a preferred embodiment, R1 is H.
In another embodiment, the 2xe2x80x2-deoxy-xcex2-L-erythro-pentofuranonucleoside derivative is xcex2-L-2xe2x80x2-deoxyuridine or pharmaceutically acceptable salt or prodrug thereof of the formula: 
wherein R1 is H, mono, di or tri phosphate, acyl, alkyl, or a stabilized phosphate derivative (to form a stabilized nucleotide prodrug).
In another embodiment, the 2xe2x80x2-deoxy-xcex2-L-erythro-pentofuranonucleoside derivative is xcex2-L-thymidine or a pharmaceutically acceptable salt or prodrug thereof of the formula: 
wherein R1 is H, mono, di or tri phosphate, acyl, alkyl, or a stabilized phosphate derivative (to form a stabilized nucleotide prodrug).
In a preferred embodiment, R1 is H.
In another embodiment, the 2xe2x80x2-deoxy-xcex2-L-erythro-pentofuranonucleoside, its pharmaceutically acceptable salt or prodrug thereof, is administered in alternation or combination with one or more other 2xe2x80x2-deoxy-xcex2-L-erythro-pentofuranonucleosides, its pharmaceutically acceptable salt or prodrug thereof, or one or more other compounds which exhibit activity against hepatitis D virus. In general, during alternation therapy, an effective dosage of each agent is administered serially, whereas in combination therapy, an effective dosage of two or more agents is administered together. The dosages will depend on absorption, inactivation, and excretion rates of the drug as well as other factors known to those of skill in the art. It is to be noted that dosage values will also vary with the severity of the condition to be alleviated. It is to be further understood that for any particular subject, specific dosage regimens and schedules should be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the compositions.
In another embodiment, the invention includes a method for the treatment of humans infected with HDV that includes administering an HDV treatment amount of a prodrug of the disclosed 2xe2x80x2-deoxy-xcex2-L-erythro-pentofuranonucleoside derivatives. A prodrug, as used herein, refers to a compound that is converted into the nucleoside on administration in vivo. Nonlimiting examples include pharmaceutically acceptable salt (alternatively referred to as xe2x80x9cphysiologically acceptable saltsxe2x80x9d), the 5xe2x80x2, N4 (cytidine) and/or N6 (adenosine) acylated or alkylated derivatives of the active compound, the 5xe2x80x2-phospholipid, and/or the 5xe2x80x2-ether lipids of the active compound.
In a preferred embodiment, the 2xe2x80x2-deoxy-xcex2-L-erythro-pentofuranonucleoside is in the form of a pharmaceutically acceptable prodrug, in that the 5xe2x80x2-hydroxyl is acylated with an amino acid. In an even more preferred embodiment, the amino acid is valine.